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Polymorphs of 1-cyclopropyl-7-([s,s])-2,8-diazadicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro -8-methoxy-4-oxo-3-quinoline carboxylic acid hydrochloride and methods for the preparation thereof

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Polymorphs of 1-cyclopropyl-7-([s,s])-2,8-diazadicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro -8-methoxy-4-oxo-3-quinoline carboxylic acid hydrochloride and methods for the preparation thereof


f) isolating the product (form B). e) reslurrying the solid at reflux in a solvent selected from alcohols and polyols or mixtures thereof, in which the resulting mixture has an overall water content of between 2.5% and 0.01% by weight, d) isolating the product which is separated, (form A) and, additionally, c) cooling, b) heating the mixture under reflux, a) suspending 1-cyclopropyl-7-([S,S])-2,8-diazabicyclo-[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid hydrochloride in a solvent selected from an alcohol and a polyalcohol, the preparation thereof, and their pharmaceutical compositions are described. These crystalline forms, which are characterized by greater stability and ease of preparation and of formulation, can be produced by industrially applicable methods which comprise the steps of: Two novel crystalline forms, designated form A and form B of the antibacterial agent 1-cyclopropyl-7-([S,S])-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid hydrochloride of formula,

Browse recent Chemi S.p.a. patents - Cinisello Balsamo (mi), IT
Inventors: Stefano TURCHETTA, Pietro MASSARDO, Valentina AROMATARIO
USPTO Applicaton #: #20120277263 - Class: 514300 (USPTO) - 11/01/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai >Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms >Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos >Bicyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos >Plural Hetero Atoms In The Bicyclo Ring System

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The Patent Description & Claims data below is from USPTO Patent Application 20120277263, Polymorphs of 1-cyclopropyl-7-([s,s])-2,8-diazadicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro -8-methoxy-4-oxo-3-quinoline carboxylic acid hydrochloride and methods for the preparation thereof.

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CROSS-REFERENCE

This application is a divisional of U.S. application Ser. No. 10/580,173 filed May 22, 2006, which is a 371 National Stage of PCT/EP2004/052699, filed Oct. 28, 2004, which claims priority and the benefit of U.S. Provisional Application Ser. No. 60/532,779 filed Dec. 24, 2003 and Italian Application No. M12003A002259 filed Nov. 20, 2003, the content of which applications are incorporated herein in their entirety.

FIELD OF THE INVENTION

The present invention relates to two novel polymorphs of 1-cyclopropyl-7-([S,S])-2,8-diazabicyclo[4.3.0]-non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid hydrochloride, the methods for the preparation thereof, and pharmaceutical formulations which include them.

STATE OF THE ART

1-cyclopropyl-7-([S,S])-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid hydrochloride, also known by the name moxifloxacin hydrochloride, is an antibacterial agent of formula:

which is widely used therapeutically in the treatment of infections by antibiotic-resistant bacteria.

Its preparation is reported in EP550903 and the preparation and characteristics of its monohydrate pseudopolymorph are described in U.S. Pat. No. 5,849,752. It is clear from this patent that the only known forms of moxifloxacin hydrochloride are the anhydrous form and the monohydrate, extensive identifying documentation of which is provided. In the patent, it is also written that the anhydrous form of the active ingredient is unsuitable for the preparation of pharmaceutical formulations since it absorbs water from the atmosphere. The monohydrate form, on the other hand, does not have the disadvantage of being hygroscopic and can be prepared in the form of crystalline prisms, which confer on the powder characteristics of fluidity that are advantageous for formulation purposes, or in the form of needles which tend rather to clump together.

According to the US patent, the monohydrate in prism form can be produced by suspending moxifloxacin hydrochloride in ethanol/water mixtures containing up to 10% of water whereas, to form the monohydrate in needle form, water or any water/alcohol mixture with a water content greater than 10% may be used.

It is also mentioned in the description of the invention that, in order to produce the monohydrate form, the relative humidity value should not fall below 30% during the drying stage, since this condition would lead to the formation of the anhydrous form.

However, the examples of the preparation of moxifloxacin hydrochloride monohydrate given in U.S. Pat. No. 5,849,752 show serious limitations of industrial applicability both owing to the large volumes of solvent that are used and owing to the subsequent production technique.

In fact the method provides first of all for the anhydrous form of moxifloxacin hydrochloride to be dissolved in a large quantity of solvent and then for the solvent to be evaporated completely so that the active ingredient is recovered as the evaporation residue. However, if this evaporation to dryness is performed hot, for example, by heating to 60-70° C., it may lead to degradation of the product whereas, if it is performed spontaneously at room temperature as described in Examples 5 and 6 of the US patent, it requires very long periods of time that are not practicable industrially.

In conclusion, there is at the moment still a need to identify an industrially applicable method of producing a stable and easily formulated form of moxifloxacin hydrochloride which does not require laborious stages for the evaporation of large volumes of solvent and which is sufficiently quick and gentle not to lead to alterations in the final product.

DESCRIPTION OF THE INVENTION

The subjects of the present invention are therefore two novel, stable, and easily formulated crystalline forms of moxifloxacin hydrochloride, a method for the preparation thereof, and pharmaceutical formulations which include them. It has in fact surprisingly been found that, by means of an easily industrially applicable method which comprises the steps of: a) suspending moxifloxacin hydrochloride in a suitable solvent, b) heating the mixture under reflux, c) cooling, and d) isolating the product which is separated, a novel hydrated crystalline form of moxifloxacin hydrochloride which is stable and easy to formulate, designated as moxifloxacin hydrochloride form A is obtained. Further, by subjecting the product resulting form the above step d) to the following additional stages characterized by e) reslurrying the solid in a suitable solvent, and f) isolating the product, another novel form of moxifloxacin hydrochloride, named form B, stable and easy to formulate too, is prepared.

The starting moxifloxacin hydrochloride may be either in amorphous form or in any crystalline form, for example, in anhydrous or monohydrate crystalline form, as described in U.S. Pat. No. 5,849,752. Preferably, the starting moxifloxacin hydrochloride is an anhydrous form having a water content of less than 0.3%.

The solvent used in the method described above is generally an alcohol or a polyol, preferably a C1-C6 alcohol or polyol, for example, methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, terbutanol, n-pentanol, n-hexanol, 1,2-ethandiol, 1,2-propandiol, 1,3-propandiol, methoxyethanol, methoxypropanol, etc. . . . , most preferably ethanol or isopropanol, or mixtures thereof.

In particular, the novel crystalline forms of moxifloxacin hydrochloride can be produced, in accordance with the above-described steps, by the suspension of moxifloxacin hydrochloride in the preselected solvent, provided that the resulting mixture has an overall water content of between 2.5% and 0.01% by weight. “Overall water content” means the quantity of water resulting from the sum of the water content of the starting moxifloxacin hydrochloride and of the water contained in the solvent.

Preferably, a solvent with a water content of between 1% and 0.01%, more preferably between 0.3% and 0.01%, and even more preferably between 0.1 and 0.01% is used.

The production of these novel crystalline forms is particularly surprising in the light of the misleading teaching provided by the U.S. Pat. No. 5,849,752; in fact in the description thereof (col. 2, lines 62-65) it is stated that “the preferred monohydrate form in the form of prisms can be obtained by suspending the crystalline anhydrous product in ethanol/water mixtures, particularly in the said mixtures with a maximum water content of 100”, thus meaning also mixtures with 2.50, 10 or 0.1% of water. In fact, in these conditions, it has surprisingly been found that, instead of the prism form described by the US patent, form A or, following the additional steps e)-f), form B, which are the subject of the present invention, are obtained.

In the method for the preparation of form A, the solvent is generally used in a ratio of between 50:1 and 2:1, preferably between 30:1 and 5:1, more preferably about 10:1, the ratio being expressed as ml of solvent per gram of moxifloxacin hydrochloride.

The mixture of moxifloxacin hydrochloride and solvent is kept under reflux (step a) for a variable period of time which will depend on various factors such as, for example, the type of solvent, the form of the starting product, the total quantity of water, etc., and is preferably at least 1 hour, more preferably about 4 hours.

The cooling of the mixture (step b) may be spontaneous or accelerated by appropriate means known to a person skilled in the art. The mixture may be cooled to room temperature or cooling may continue to lower temperatures; in general, it is preferred to allow the mixture to cool spontaneously until room temperature is reached.

In a particularly preferred method, cooling to room temperature takes place in about 2 hours and the mixture is allowed to rest at that temperature for a further 2 hours before the isolation is performed.

The novel crystalline forms according to the invention are isolated by conventional techniques, for example, by filtration, decantation or centrifuging.

The novel crystalline form A of moxifloxacin hydrochloride is characterized by the X-ray diffraction spectrum (XRD) which is shown in FIG. 1 and described in Table 1, by the solid-state 13C-NMR spectrum which is shown in FIG. 2 and tabulated in Table 2, by the IR spectrum which is given in FIG. 3, and by the DSC trace which is shown in FIG. 4. The differences in comparison with the known forms can clearly be distinguished by comparing this spectral data with those of the anhydrous and monohydrate forms described in U.S. Pat. No. 5,849,752. In particular, in the XRD spectrum of the novel form, characteristic peaks situated at 7.2, 12.3, 16.6 and 21.6 are distinguished and, in the solid-state 13C-NMR spectrum, characteristic peaks are shown at 169.1, 164.6, 151.8, 115.7 and 67.7, as results from the following table:

TABLE 1

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stats Patent Info
Application #
US 20120277263 A1
Publish Date
11/01/2012
Document #
13538249
File Date
06/29/2012
USPTO Class
514300
Other USPTO Classes
546113
International Class
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